From the Department of Neurosurgery, Faculty of Medicine (H.H., A.M., H.T., W.T., Y.M., T.Y., A.M.), Department of Neurosurgery, Graduate School of Comprehensive Human Science (H.H., A. Marushima, A. Mujagic, H.T., W.T., Y.M., T.Y., A.M.), Graduate School of Pure and Applied Sciences (Y.N.), Department of Gastroenterology, Graduate School of Comprehensive Human Science (H.I., H.M.), and Graduate School of Systems and Information Engineering (S.P.), University of Tsukuba, Ibaraki, Japan; Center for Integrative Medicine, Tsukuba University of Technology, Ibaraki, Japan (A.H.); and Department of Neurosurgery, Dokkyo Medical University Koshigaya Hospital, Saitama, Japan (K.S.).
Stroke. 2017 Aug;48(8):2238-2247. doi: 10.1161/STROKEAHA.116.016356. Epub 2017 Jun 27.
Reperfusion therapy by mechanical thrombectomy is used to treat acute ischemic stroke. However, reactive oxygen species generation after reperfusion therapy causes cerebral ischemia-reperfusion injury, which aggravates cerebral infarction. There is limited evidence for clinical efficacy in stroke for antioxidants. Here, we developed a novel core-shell type nanoparticle containing 4-amino-4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (nitroxide radical-containing nanoparticles [RNPs]) and investigated its ability to scavenge reactive oxygen species and confer neuroprotection.
C57BL/6J mice underwent transient middle cerebral artery occlusion and then received RNPs (9 mg/kg) through the common carotid artery. Infarction size, neurological scale, and blood-brain barrier damage were visualized by Evans blue extravasation 24 hours after reperfusion. RNP distribution was detected by rhodamine labeling. Blood-brain barrier damage, neuronal apoptosis, and oxidative neuronal cell damage were evaluated in ischemic brains. Multiple free radical-scavenging capacities were analyzed by an electron paramagnetic resonance-based method.
RNPs were detected in endothelial cells and around neuronal cells in the ischemic lesion. Infarction size, neurological scale, and Evans blue extravasation were significantly lower after RNP treatment. RNP treatment preserved the endothelium and endothelial tight junctions in the ischemic brain; neuronal apoptosis, O production, and gene oxidation were significantly suppressed. Reactive oxygen species scavenging capacities against OH, ROO, and O improved by RNP treatment.
An intra-arterial RNP injection after cerebral ischemia-reperfusion injury reduced blood-brain barrier damage and infarction volume by improving multiple reactive oxygen species scavenging capacities. Therefore, RNPs can provide neurovascular unit protection.
机械取栓再灌注疗法用于治疗急性缺血性脑卒中。然而，再灌注治疗后活性氧的产生会导致脑缺血再灌注损伤，从而加重脑梗死。抗氧化剂在脑卒中的临床疗效证据有限。在这里，我们开发了一种新型的核壳型纳米颗粒，包含 4-氨基-4-羟基-2,2,6,6-四甲基哌啶-1-氧自由基（含氮氧自由基纳米颗粒[RNP]），并研究了其清除活性氧和提供神经保护的能力。
C57BL/6J 小鼠进行短暂性大脑中动脉闭塞，然后通过颈总动脉给予 RNP（9mg/kg）。再灌注 24 小时后通过 Evans 蓝渗出评估梗死面积、神经评分和血脑屏障损伤。通过 rhodamine 标记检测 RNP 分布。评估缺血脑内血脑屏障损伤、神经元凋亡和氧化神经元细胞损伤。通过基于电子顺磁共振的方法分析多种自由基清除能力。
RNP 在内皮细胞和缺血性病变中的神经元细胞周围被检测到。RNP 治疗后梗死面积、神经评分和 Evans 蓝渗出明显降低。RNP 治疗可保护缺血脑内的内皮细胞和内皮紧密连接；神经元凋亡、O 生成和基因氧化明显受到抑制。RNP 治疗可改善对 OH、ROO 和 O 的活性氧清除能力。
脑缺血再灌注损伤后经动脉内 RNP 注射可通过提高多种活性氧清除能力来减少血脑屏障损伤和梗死体积。因此，RNP 可以提供神经血管单元保护。
